Abstract
The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient–mTORC1 signalling in multiple diseases.
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Change history
26 September 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41580-023-00670-3
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Acknowledgements
This work was supported by National Institutes of Health (NIH) R01CA260205 and the Edward Mallinckrodt, Jr Foundation Scholar Award to R.Z., and by an Italian Association for Cancer Research (AIRC) fellowship to R.P.
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Glossary
- β-Meander
-
A frequent protein motif characterized by a particular type of antiparallel β-sheet structure, in which two or more β-strands are consecutive in sequence and adjacent to one another in the three-dimensional structure.
- C 2 symmetry
-
C2 is a crystallography point group symbol of a dimeric protein composed of two identical chains, implying the presence of ‘cyclic’ symmetry with a single twofold axis.
- Coatomer
-
A protein complex that coats membrane-bound transport vesicles, characterized by the combination of β-propeller and α-solenoid domains as building blocks of large multiprotein assemblies.
- Lysosomal limiting membrane
-
A membrane that distinguishes the acidic lumen of the lysosome from the cytosol.
- Mitochondrial poisoning
-
Refers to the use of different drugs (for example, electron transport inhibitors) that reduce mitochondrial function by altering the mitochondrial membrane potential and decreasing mitochondrial ATP production.
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Goul, C., Peruzzo, R. & Zoncu, R. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease. Nat Rev Mol Cell Biol 24, 857–875 (2023). https://doi.org/10.1038/s41580-023-00641-8
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DOI: https://doi.org/10.1038/s41580-023-00641-8
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